Pharmacogenetics: a drug for each person

Sometimes, some people say that the medications prescribed by doctors are not good. Can this be true? Not all drugs work for the same population. Keep reading and discover the secrets of pharmacogenetics.

INTRODUCTION

The same that happens with nutrients, happens with drugs. Another objective of personalized medicine is to make us see that not all medicines are for everyone. However, it does not come again because around 1900, the Canadian physician William Osler recognized that there was an intrinsic and specific variability of everyone, so that each one reacts differently to a drug. This is how, years later, we would define pharmacogenetics.

It is important to point out that it is not the same as pharmacogenomics, which studies the molecular and genetic bases of diseases to develop new treatment routes.

First, we need to start at the beginning: what is a drug? Well, a drug is any physicochemical substance that interacts with the body and modifies it, to try to cure, prevent or diagnose a disease. It is important to know that drugs regulate functions that our cells do, but they are not capable of creating new functions.

Apart from knowing if a drug is good or not for a person, you also have to take into account the amount that should be administered. And we still do not know the origin of all diseases, that is, we do not know most of the real molecular and genetic causes of diseases.

The classification of diseases is based mainly on symptoms and signs and not on molecular causes. Sometimes, the same group of pathologies is grouped, but among them there is a very different molecular basis. This means that the therapeutic efficacy is limited and low. Faced with drugs, we can manifest a response, a partial response, that produces no effect or that the effect is toxic (Figure 1).

Figure 1. Drug toxicity. Different colours show possible responses (green: drug not toxic and beneficial; blue: drug not toxic and not beneficial; red: drug toxic but not beneficial; yellow: drug toxic but beneficial) (Source: Mireia Ramos, All You Need is Biology)

DRUGS IN OUR BODY

Drugs usually make the same journey through our body. When we take a drug, usually through the digestive tract, it is absorbed by our body and goes to the bloodstream. The blood distributes it to the target tissues where it must take effect. In this case we talk about active drug (Figure 2). But this is not always the case, but sometimes it needs to be activated. That’s when we talk about a prodrug, which needs to stop in the liver before it reaches the bloodstream.

Most of the time, the drug we ingest is active and does not need to visit the liver.

Figure 2. Difference between prodrug and active drug (Source: Agent of Chemistry – Roger Tam)

Once the drug has already gone to the target tissue and has interacted with target cells, drug waste is produced. These wastes continue to circulate in the blood to the liver, which metabolizes them to be expelled through one of the two routes of expulsion: (i) bile and excretion together with the excrement or (ii) purification of the blood by the kidneys and the urine.

THE IMPORTANCE OF PHARMACOGENETICS

A clear example of how according to the polymorphisms of the population there will be different response variability we find in the transporter genes. P glycoprotein is a protein located in the cell membrane, which acts as a pump for the expulsion of xenobiotics to the outside of the cell, that is, all chemical compounds that are not part of the composition of living organisms.

Humans present a polymorphism that has been very studied. Depending on the polymorphism that everyone possesses, the transporter protein will have normal, intermediate or low activity.

In a normal situation, the transporter protein produces a high excretion of the drug. In this case, the person is a carrier of the CC allele (two cytokines). But if you only have one cytosine, combined with one thymine (both are pyrimidine bases), the expression of the gene is not as good, and the expulsion activity is lower, giving an intermediate situation. In contrast, if a person has two thymines (TT), the expression of the P glycoprotein in the cell membrane will be low. This will suppose a smaller activity of the responsible gene and, consequently, greater absorption in blood since the drug is not excreted. This polymorphism, the TT polymorphism, is dangerous for the patient, since it passes a lot of drug to the blood, being toxic for the patient. Therefore, if the patient is TT the dose will have to be lower.

This example shows us that knowing the genome of each individual and how their genetic code acts based on it, we can know if the administration of a drug to an individual will be appropriate or not. And based on this, we can prescribe another medication that is better suited to this person’s genetics.

 APPLICATIONS OF THE PHARMACOGENETICS

The applications of these disciplines of precision medicine are many. Among them are optimizing the dose, choosing the right drug, giving a prognosis of the patient, diagnosing them, applying gene therapy, monitoring the progress of a person, developing new drugs and predicting possible adverse responses.

The advances that have taken place in genomics, the design of drugs, therapies and diagnostics for different pathologies, have advanced markedly in recent years, and have given way to the birth of a medicine more adapted to the characteristics of each patient. We are, therefore, on the threshold of a new way of understanding diseases and medicine.

And this occurs at a time when you want to leave behind the world of patients who, in the face of illness or discomfort, are treated and diagnosed in the same way. By routine, they are prescribed the same medications and doses. For this reason, the need has arisen for a scientific alternative that, based on the genetic code, offers to treat the patient individually.

REFERENCES

• Goldstein, DB et al. (2003) Pharmacogenetics goes genomic. Nature Review Genetics 4:937-947
• Roden, DM et al. (2002) The genetic basis of variability in drug responses. Nature Reviews Drug Discovery 1:37-44
• Wang, L (2010) Pharmacogenomics: a system approach. Syst Biol Med 2:3-22
• Ramos, M. et al. (2017) El código genético, el secreto de la vida. RBA Libros
• Main picture: Duke Center for Applied Genomics & Precision Medicine

 

What is gene therapy?

In the last years we have heard discuss gene therapy and its potential. However, do we know what gene therapy is? In this article, I want to make known this promising tool that can cure some diseases that therapies with conventional drugs cannot it. I discuss approaches of gene therapy and their key aspects, where we find animal models.

INTRODUCTION

A clinical trial is an experimental study realized in patients and healthy subjects with the goal to evaluate the efficiency and/or security of one or various therapeutics procedures and, also, to know the effects produced in the human organism.

Since the first human trial in 1990, gene therapy has generated great expectations in society. After over 20 years, there are a lot of gene therapy protocols have reached the clinical stage.

Before applying gene therapy in humans it is necessary to do preclinical studies; these are in vitro or in vivo investigations before moving to clinical trials with humans. The aim of these is protect humans of toxic effects that the studied drug may have.

An important element in preclinical studies are animal models. First, tests are made with small animals like mice. If they are successful, then tests are made with larger animals, like dogs. Finally, if these studies give good results then they are passed to higher animals: primates or humans.

WHAT IS GENE THERAPY?

Gene therapy represents a promising tool to cure some of those diseases that conventional drug therapies cannot. This therapy consists in the transfer of genetic material into cells or tissues to prevent or cure a disease.

Initially gene therapy was established to treat patients with hereditary diseases caused by single gene defects, but now, at present, many gene therapy efforts are also focused on curing polygenic or non-inherited diseases with high prevalence (Video 1).

Video 1. Explanation about what gene therapy is (Source: YouTube)

APPROACHES IN GENE THERAPY

There are two types of approaches in gene therapy (Figure 1):

• In vivo gene therapy: introduce a therapeutic gene into a vector which then is administered directly to the patient. The vector will transfer the gene of interest in the target tissue to produce the therapeutic protein.
• Ex vivo gene therapy: transfer the vector carrying the therapeutic gene into cultured cells from the patient. After, these genetically engineered cells are reintroduced to the patients where they now express the therapeutic protein.

Figure 1. Differences between the two types of approaches in gene therapy (Source: CliniGene – Gene Therapy European Network)

KEY ASPECTS OF GENE THERAPY

When designing a gene therapy approach there are some key aspects to be considered:

1/ THERAPEUTIC GENE

The gene of interest is that which is introduced into the body to counteract the disease. For the one hand, for the diseases are caused by the lost or dysfunction of a single protein, the gene to be transferred is more identifiable, being that only a correct copy of the gene whose dysfunction causes the diseases will be introduced. For the other hand, for the diseases whose origin is more complex the choice of the therapeutic gene may be more difficult and will have to make several studies and know well the disease.

2/ VECTOR

Vehicle by which the gene of interest is transported to the target cells. The perfect vector should be able to transduce target cells without activating an immune response either against itself or the therapeutic gene. But there aren’t a universal vector to treat any disease.

2.1/ VIRAL VECTORS

These type of vectors derives from viruses, but this is not a problem because much or all of the viral genes are replaced by the therapeutic gene. This means that the viral vectors do not cause pathogenic disease because the gene was deleted.

2.2/ NON-VIRAL VECTORS

These type of vectors does not derive from viruses, but the therapeutic gene is part of a plasmid.

3/ TARGET CELLS

Any cell that has a specific receptor for an antigen or antibody, or hormone or drug… The therapeutic gene must be directed to target cells in specific tissues.

4/ ROUTES OF ADMINISTRATION

The therapeutic gene must be administered through the most appropriate route. The type of route depends, as like as vector, the target tissue, the organ to manipulate or the disease to be treated.

5/ ANIMAL MODELS

Are used to find out what happens in a living organism. They are mainly used in research to achieve progress of scientific knowledge, as many basic cellular processes are the same in all animals and can understand what happens to the body when it has a defect; as models for the study of a disease, because humans and animals share many diseases and how to respond to the immune system; to develop and test potential methods of treatment, being an essential part of applying biological research to real medical problems and allowing the identification of new targets for the intervention of the disease; and, finally, to protect the safety of people, animals and environment, researchers have measured the effects of beneficial and harmful compound on an organism, identifying possible problems and determine the dose administration.

Gene therapy represents a promising tool to cure some of those diseases that conventional drug therapies cannot. The availability of animal models is key to preclinical phases because it allows thorough evaluation of safety and efficacy of gene therapy protocols prior to any human clinical trials.

In the near future, gene therapy will be an effective alternative to pharmacological efforts, and enable treatment of many diseases that are refractory or not suitable for pharmacologic treatment alone. Thus, gene therapy is a therapeutic tool that gives us virtually unlimited possibilities to develop better and more effective therapies for previously incurable diseases.

REFERENCES

• Ramos Muntada M. “Animal Models for Gene Therapy of Glycogenosis” Final Degree Project. UAB, Genetics Bachelor’s Degree 2015
• Bosch F, Roca C, Anguela X and Ruzo A. “Gene Therapy, a new tool to cure human diseases” CliniGene-NoE. CBATEG-UAB 2011, CliniGene – Gene Therapy European Network
• Gene Therapy Technology Explained
• Australian Clinical Trials
• Main picture: Genetic Literacy Project